bardoxolone methyl (RTA 402) / Kyowa Kirin, Biogen - LARVOL DELTA

The antiproliferative and pro-apoptotic effects of 3-deoxy-3α-fluoro-chenodeoxycholic acid and 12β-methyl-3,7-dioxo-17-epi-25-homo-18-nor-5β-cholan-25-oic acid on human breast cancer cell lines. (PubMed, Bioorg Med Chem Lett) - "The anti-proliferative activities of nine synthesised derivatives, as well as bardoxolone methyl (CDDO-Me) which is a well-characterised IκB kinase (IKK) and NF-κB inhibitor and Nrf2 activator, were assessed in vitro against two clinically relevant breast cancer cell lines: MCF-7 (estrogen receptor-positive) and MDA-MB-231 (triple negative)...We further discuss structure-activity relationships for these compounds and show that they cause cell death in both cell lines via a statistically significant induction of apoptosis. In addition, in silico assessment predicted appropriate ADMET properties and compliance with Lipinski's rule of five."

Journal • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER

Bardoxolone methyl exerts an inhibitory effect on respiratory syncytial virus infection by downregulating IL-6 via the IKKβ/NF-κB signaling pathway. (PubMed, Microbiol Spectr) - "Importantly, our findings suggest that BXM acts, at least in part, by reducing IL-6-related inflammatory signaling, which is closely associated with RSV disease severity. These results provide experimental evidence supporting BXM as a promising candidate for further development against RSV infection and offer insight into a potential host-targeted therapeutic strategy."

Journal • Infectious Disease • Inflammation • Respiratory Diseases • Respiratory Syncytial Virus Infections • IL6

Inflammation as a therapeutic target to improve kidney and cardiovascular outcomes. (PubMed, Nat Rev Nephrol) - "Investigational treatments that have targeted inflammation include inhibition of apoptosis signal-regulating kinase-1 (ASK1) by selonsertib, Janus kinase (JAK) 1/2 inhibition with baricitinib, protein kinase C-β (PKCβ) inhibition with ruboxistaurin, nuclear factor erythroid 2-related factor 2 (Nrf2) activation with bardoxolone, phosphodiesterase inhibition with pentoxifylline and monoclonal antibodies against IL-1β and IL-6. Furthermore, proven therapies for CKD, including renin-angiotensin-aldosterone system inhibitors, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists and non-steroidal mineralocorticoid antagonists, possess anti-inflammatory properties that might contribute to their previously established clinical benefits."

Journal • Review • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Inflammation • Nephrology • Renal Disease • CRP • IL1B • IL6 • PRKCB

Bardoxolone methyl induces mitochondrial dysfunction, activation of the cytosolic stress response, and increased chaperone capacity in SH-SY5Y cells. Focus on mitochondrial protease LONP1. (PubMed, Gen Physiol Biophys) - "Finally, we have observed the formation of donut-like mitochondria induced by CDDO-Me. Our results, together with previously published data, indicate that mitochondrial dysfunction, activation of cytosolic stress response, and an increase in chaperone capacity elicited by CDDO-Me could be attributed to CDDO-Me's ability to inhibit LONP1 protease."

Journal • Metabolic Disorders • GSDME • HSPA5 • HSPA9 • HSPD1 • LONP1

Drug failure in diabetic kidney disease: translational barriers, target validation and trial de-risking strategies. (PubMed, Biochem Pharmacol) - "We compare successful development paths for SGLT2 inhibitors, finerenone and semaglutide with constrained or unsuccessful programmes involving dual RAAS blockade, bardoxolone methyl, endothelin receptor antagonists, apoptosis signal-regulating kinase 1 (ASK1) inhibition, immunomodulation, sulodexide and pyridoxamine. Across these examples, recurring vulnerabilities emerge in human target validation, animal-to-human translation, renal exposure, target engagement, pharmacodynamic biomarker selection, patient enrichment, endpoint choice and safety-constrained dosing. We propose a de-risking framework that prioritizes human tissue evidence, renal cell-specific causal validation, pharmacokinetic and pharmacodynamic integration, mechanism-aligned biomarkers, adaptive trial design and biology-guided patient selection."

Journal • Review • Acute Kidney Injury • Cardiovascular • Congestive Heart Failure • Diabetic Nephropathy • Heart Failure • Hematological Disorders • Immunology • Nephrology • Renal Disease

CDDO-Me Overcomes Gefitinib Resistance in NSCLC by Targeting the Src/STAT3 Axis to Induce Apoptosis and Pyroptosis. (PubMed, Int J Mol Sci) - "Collectively, these findings suggest that CDDO-Me enhances gefitinib sensitivity by targeting Src and suppressing Src/STAT3 signaling, leading to apoptosis and pyroptosis in gefitinib-resistant NSCLC cells. This study provides mechanistic evidence for further investigation of CDDO-Me-based combination strategies for gefitinib-resistant NSCLC."

Journal • Lung Cancer • Metabolic Disorders • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CASP3 • GSDME

Species, cell proliferation state and oxygen partial pressure are major factors in the in vitro toxicity of repurposed potential ADPKD drugs in human and murine renal proximal tubule cells. (PubMed, Arch Toxicol) - "In a quest for potential alternatives to tolvaptan, we compared the nephrotoxic and metabolic effects of four repurposed drugs, salicylic acid (up to 10 mM), birinapant (up to 100 µM), bardoxolone methyl (up to 1000 nM), and rapamycin (up to 160 nM) to tolvaptan (up to 100 µM) on human differentiated and proliferating (RPTEC/TERT1) and mouse proliferating (mProx24) renal proximal tubular epithelial cells at atmospheric (21%) and physiological (10%) O2 tensions. The focus was on improved interpretation of in vitro test results for the detection of potential adverse effects. We found that cell proliferation and O2 tension are major factors that determine the susceptibility of cells to compounds, while the drug effects on the metabolism and mitochondrial function provided further insight into the mechanisms underlying the observed in vitro toxicity."

Journal • Preclinical • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Redox-sensitive GPCR signaling drives Gq-dependent Ca²⁺ mobilization and cytokine production in human bronchial epithelial cells. (PubMed, Am J Physiol Cell Physiol) - "Antioxidant scavenger pretreatment (glutathione, N-acetylcysteine) markedly attenuated both ROS production and Ca²⁺ mobilization, whereas induction of endogenous antioxidant defenses with bardoxolone abolished the response, indicating redox sensitivity. Pharmacologic inhibition of Gqα with YM-254890 suppressed both phases of the Ca²⁺ response, implicating Gq-coupled receptor activation...ELISA confirmed increased secretion of IL-1β, IL-6, IL-8, and IL-33, with differential sensitivity to PKC isoforms and NF-κB inhibition. These findings identify a redox-sensitive GPCR network that amplifies Gq-dependent Ca²⁺ signaling in airway epithelial cells and provides a mechanistic framework for epithelial inflammatory activation following ROS-inducing environmental exposures."

Journal • Inflammation • Respiratory Diseases • CXCL8 • CYSLTR2 • IL1B • IL33 • IL6 • TNFA

Differential KEAP1/NRF2 signaling widens therapeutic window of TXNRD1 inhibitors in SCLC therapy (EACR 2026) - "Introduction: Small cell lung cancer (SCLC) is characterized by high initial sensitivity to cisplatin/etoposide but rapid relapse, with no effective maintenance therapies available. Low, non-inducible ROS-buffering capacity is an Achilles heel of SCLC. TXNRD1 inhibition offers subtype-independent maintenance therapy, enhanced by selective NRF2 activation in normal tissues to widen the therapeutic window."

Lung Cancer • Small Cell Lung Cancer • Solid Tumor • KEAP1

Bardoxolone methyl modulates Nrf2/NF- (PubMed, Biol Reprod) - "Turkey uterovaginal junction (UVJ) organoids were treated with BM and exposed to oxidant hydrogen peroxide. Treatment with 0.5 μM BM increased viability, reduced reactive oxygen species production, and inhibited nuclear translocation of NF-"

Journal • Inflammation • Metabolic Disorders

Identification of drug repurposing candidates for the treatment of polycystic kidney disease. (PubMed, Br J Pharmacol) - "We have identified novel targets of three repurposing candidates that contribute to the cyst growth reducing effects in preclinical ADPKD models and identify salicylic acid, the metabolite of aspirin, as the repurposing candidate with the most promising mechanisms of action."

Journal • Autosomal Dominant Polycystic Kidney Disease • Chronic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Development of a multimodal pipeline to identify novel 14-3-3zeta inhibitors that can block adipogenesis to treat obesity (ECO 2026) - "All drugs were tested at 1 or 10 μM, and differentiation was induced with a cocktail of insulin, IBMX, and dexamethasone. Our study reports of a novel pipeline to discover 14-3-3zeta inhibitors that could serve as anti-obesity medications or be used with larger compound libraries. Bardoxolone methyl and Ponatinib were identified as potential AOMs that could be combined with existing approaches, such as incretin-based drugs, to augment weight loss. Conflicts of Interest & Funding: GEL was a consultant for Ambagon TX and has received research support from Inversago Pharma, a Novo Nordisk Company."

Diabetes • Genetic Disorders • Obesity • Type 2 Diabetes Mellitus • PPARG

The Mechanisms and Treatment Approaches of Oxidative Stress and Inflammation in the Development of Chronic Kidney Disease. (PubMed, Curr Hypertens Rev) - "Therapeutic strategies for CKD are categorized into three main approaches: antioxidants and anti-inflammatory medications, SGLT2 inhibitors, and bardoxolone methyl. The article also emphasizes non-pharmacological interventions, including behavioral modifications, dietary adjustments, probiotic use, and modulation of the gut microbiota. Finally, it discusses emerging research on biomarker development, precision medicine techniques, and genetic therapies aimed at improving CKD detection, management, and treatment outcomes."

Journal • Cardiovascular • Chronic Kidney Disease • Fibrosis • Gene Therapies • Immunology • Inflammation • Metabolic Disorders • Nephrology • Orthopedics • Renal Disease

The AMPK/NRF2/FOXO Axis in CKD-Molecular and Clinical Perspectives. (PubMed, Antioxidants (Basel)) - "We highlight the functional paradoxes within the axis and evaluate the benefits and drawbacks of nutraceuticals and pharmacological agents, such as NRF2 inducer bardoxolone methyl, underscoring the necessity for context-dependent modulation. Furthermore, we examine the AMPK-NRF2-FOXO axis within the current clinical management, according to the 2024/2026 KDIGO guidelines. These guidelines reflect a shift toward a multi-targeted pharmacological approach involving metformin, SGLT2 inhibitors, GLP-1 receptor agonists, finerenone, and hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors."

Journal • Review • Chronic Kidney Disease • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • AMPK

Downregulation of hepatic CYP3A isoforms by bardoxolone methyl in rats and its impact on in vivo metabolic capacity reflecting pharmacokinetics. (PubMed, Sci Rep) - "This study investigated whether BX downregulates hepatic CYP3A expression and activity, and determine its impact on the pharmacokinetics of midazolam (MDZ), involving atypical substrate probing for CYP3A, in rats.　Male Sprague-Dawley rats received a single intraperitoneal dose of BX (10 mg/kg). In conclusion, we suggest that hepatic CYP3A expression and intrinsic metabolic capacity are suppressed by BX, thereby markedly increasing the oral bioavailability of CYP3A substrates. These findings may help in the early detection of clinically significant drug interactions between Nrf2 activators and CYP3A substrate drugs."

Journal • PK/PD data • Preclinical

Treatment Responses Alter Myeloid Activation in BRAF-Mutant Melanoma (IMMUNOLOGY 2026) - "We have shown that the addition of the synthetic triterpenoid CDDO-Me to the BRAFi PLX4720 arrested resistance and significantly reduced tumor burden, while CDDO-Me as a single agent or in combination with BRAFi prior to resistance was ineffective. The iTME changes with tumor progression and responds dynamically to BRAFi treatment and resistance. This work establishes for the first time that BRAFi promotes myeloid-mediated induction of T cell activation, which is lost at resistance but can be rescued with the addition of CDDO-Me. Because BRAFi resistance and iTME immunosuppression is reversed by CDDO-Me treatment, these results provide the foundation for its potential use in combination therapies for melanoma."

Genetic Disorders • Melanoma • Skin Cancer • Solid Tumor • BRAF • PTEN

CDDO-Me alleviates doxorubicin/lapatinib-induced cardiotoxicity by activating the NRF2/GPX4 axis to inhibit oxidative stress and ferroptosis. (PubMed, Free Radic Biol Med) - "Furthermore, CDDO-Me did not compromise the antitumor efficacy of DOX/LAP in breast cancer cells. CDDO-Me protects against DOX/LAP-induced cardiotoxicity by stabilizing GPX4 and inhibiting ferroptosis, offering a promising therapeutic strategy that preserves cardiac function without interfering with chemotherapy."

Journal • Breast Cancer • Cardiovascular • Fibrosis • Hematological Disorders • Immunology • Metabolic Disorders • Oncology • Solid Tumor • Targeted Protein Degradation • GPX4

Discovery of a Prodrug of Bardoxolone Methyl for the Treatment of Acute Lung Injury. (PubMed, ChemMedChem) - "Moreover, prodrug 2 concentration-dependently inhibited NO production in lipopolysaccharide (LPS)-stimulated cells. In an ALI mouse model, prodrug 2 exhibited therapeutic efficacy comparable to CDDO-Me and significantly attenuated the symptoms of LPS-induced lung injury."

Journal • Acute Lung Injury • Pulmonary Disease • Respiratory Diseases

Discovery of New CDDO-Imidazole Derivatives as Potential Antitumor Agents. (PubMed, ChemMedChem) - "Notably, 8 exhibited significant antitumor efficacy comparable to CDDO-Me (bardoxolone methyl), which had entered clinical trials. Taken together, 8 represents a promising candidate for the treatment of cancer and merits further study."

Journal • Oncology • BAX • BCL2 • CASP3

Inhibition of smooth muscle phenotypic modulation by bardoxolone methyl, omaveloxolone, and cinnamaldehyde is Nrf-2 dependent. (PubMed, Adv Redox Res) - "Aditionally, BAR also showed marked inhibition of hyperplasia in vivo. These findings demonstrate that these electrophilic activators suppress restenosis by stabilizing VSMC phenotype via strictly Nrf2-dependent signaling."

Journal • NQO1 • TAGLN

Targeting the Keap1-Nrf2 Axis in COPD: Comparative analysis of electrophilic and peptide-based Nrf2 activators in airway and immune cells. (PubMed, Eur J Pharmacol) - "These results confirm that the Nrf2 pathway is compromised in COPD and support selective Nrf2 activation-particularly via peptide-based approaches-as a promising therapeutic strategy to mitigate oxidative and inflammatory injury in the disease."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CXCL8 • IL6 • KEAP1 • MMP9 • NFE2L2 • NQO1

The Analgesic Effects of Nrf2 Activators in Chemotherapy-Induced Neuropathic Pain: Evidence from Animal Studies and Consequences for Translation into Clinical Trials. (PubMed, Int J Mol Sci) - "Chemotherapy-induced neuropathic pain (CINP) can be caused by several chemotherapeutic drugs, including paclitaxel, oxaliplatin, and vincristine, which is difficult to treat with several drugs, including antidepressants and anticonvulsants...Several Nrf2 activators, including tempol, oltipraz, rosiglitazone, pristimerin, cannabidiol, daidzein, bardoxolone methyl, curcumin, resveratrol, and mitoquinone, demonstrated analgesic effects in CINP animal models. Furthermore, in clinical studies, curcumin demonstrated significant efficacy in reducing vincristine-induced neuropathy in pediatric leukemia patients, while the combined administration of alpha-lipoic acid with ipidacrin hydrochloride prevented paclitaxel-induced motor neuropathy and improved axonal function in breast cancer patients. Thus, the purposes of our review article were to summarize the analgesic effects of Nrf2 activators and the patho-mechanisms of Nrf2 in CINP animal, and then the consequences for clinical..."

Journal • Review • Breast Cancer • Hematological Malignancies • Leukemia • Neuralgia • Oncology • Pain • Pediatrics • Solid Tumor

Discovery of novel Keap1-targeting hydrophobic tag (HyT) tethering degraders with potent Nrf2 activation activity. (PubMed, Eur J Med Chem) - "Mechanistic studies revealed a unique dual-pathway degradation process involving the ubiquitin-proteasome system and the autophagy-lysosome pathway. Our findings not only establish HyTTD as a viable degradation strategy for Keap1 but also identify NBE5 as a promising therapeutic candidate for redox-related pathologies such as inflammatory bowel disease."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Targeted Protein Degradation • CRBN • KEAP1

NRF2 activators and the inhibitor of nuclear export, selinexor, restrict coronaviruses by targeting a network involving ACE2, TMPRSS2, and XPO1 through an NRF2-independent mechanism. (PubMed, Commun Biol) - "We assessed the potential of the NRF2 activators 4-octyl itaconate (4OI), bardoxolone (BARD), and sulforaphane (SFN), and the exportin-1 (XPO1) blocker selinexor (SEL) to inhibit highly pathogenic (SARS-CoV-2) and seasonal (hCoV-229E) coronaviruses in cellular models. XPO1 knock-down reduces CoV-229E replication and reveals that efficacy of the compounds against CoV-229E depends on XPO1 expression in the order SEL > 4OI > SFN > BARD, suggesting that especially BARD restricts hCoV-229E via another, unknown, target. Taken together, these results suggest that "NRF2 activators" can restrict human coronaviruses by targeting an NRF2-independent network involving ACE2, TMPRSS2, and XPO1."

IO biomarker • Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Targeted Protein Degradation • XPO1

Treadmill Exercise Attenuates CUMS-Induced Depressive Behaviors by Modulating the UPRmt via the Nrf2/Keap1 Pathway. (PubMed, Brain Res Bull) - "The treadmill exercise activates the Nrf2/Keap1 pathway in the hippocampus, thereby reducing CUMS-induced excessive and dysregulated endoplasmic reticulum stress (UPRmt) in an Nrf2-dependent manner, which leads to a recovery of mitochondrial function, suppression of oxidative stress, and improvement of depressive-like behaviors."

Journal • CNS Disorders • Depression • Metabolic Disorders • Mood Disorders • Psychiatry • ATF5 • HSPD1 • LONP1 • NQO1